Elucidating the cellular mechanisms of prion propagation and clearance for devisi

阐明朊病毒传播和清除的细胞机制

• 批准号: 8663969
• 负责人: Donald L. Jarvis
• 金额: $ 30.64万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663969
• 关键词: Address; Aging; Animals; Autophagocytosis; Biological; Biology; Cells; Communicable Diseases; Data; Development; Devices; Disease; Epidemic; Equilibrium; Event; Functional disorder; Genetic; Goals; Health; In Vitro; Incidence; Infection; Intervention; Modeling; Molecular; Molecular and Cellular Biology; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathway interactions; Physiological; Physiology; PrP; PrPSc Proteins; Prion Diseases; Prions; Protein Isoforms; Proteins; Quality Control; Recycling; Research; Seeds; Societies; Sorting - Cell Movement; Therapeutic; Work; cellular targeting; fight against; in vivo; insight; man; novel; prion-like; programs; prophylactic; protein expression; protein misfolding; research study; transmission process

DESCRIPTION (provided by applicant): Elucidating the cellular mechanisms of prion propagation and clearance for devising new targets for intervention in prion disease There are an increasing number of neurodegenerative disorders which result from the aggregation of misfolded proteins and which share patho-physiological mechanisms. Prion diseases are the prototypical protein misfolding diseases, and their pathogenesis is associated solely with aberrant misfolding of a single cellular protein (PrPc). Prion diseases are unique in this group as they are infectious disorders found in man and animals. Besides sporadic or genetic manifestation, they can be acquired by infection and transmitted between species, resulting in endemic or epidemic scenarios (e.g. BSE/vCJD and CWD). They can be controlled, but eradication is impossible. Therefore, it is mandatory to understand the molecular and cellular requirements for propagation and transmission of prions in order to device rational strategies for controlling these events. Advances in understanding prion patho-physiology will have major implications for other protein misfolding diseases, as it may help elucidate common cellular mechanisms. Such understanding is of fundamental scientific importance as neurodegenerative diseases represent one of the biggest health problems in our aging society, and uncovering molecular mechanisms of general validity is fundamental for the identification of new targets and development of rational therapies. The long-term goal of our group is to develop therapeutic and prophylactic anti-prion strategies. The overall objective we have is to study the cellular and molecular biology of prion infections and to use gained understanding for delineating novel targets for intervention. We have focused our attempts on two main strategies. One is the endogenous cellular clearance capacity for prions, the other one is to target the cellular isoform PrPc, which is a prerequisite for prion conversion and execution of neurodegeneration. It is our central hypothesis that it is feasible to interfere in prion propagation by increasing the cellular clearance for prions. Work in Aim 1 will substantiate our finding that prion clearance can be enhanced by compound-induced induction of autophagy, a basic cellular program for degradation and recycling. The proposed work intends to better understand the underlying molecular mechanisms and to validate the therapeutic and translational potential of this finding in vivo. Work in Aim 2 and 3 addresses cellular modifiers of prion formation. We have found that a basal level of autophagy is needed for establishing prion infection and we propose that autophagy represents the biological equivalent for the postulated disaggregase function in mammalian prion/prion-like biology. Our goal is to prove this at the cellular and molecular level. The rational for work in Aim 3 is that protein quality control mechanisms in the secretory pathway can directly influence prion conversion by determining on the quality of conversion substrates. We want to manipulate this by over-expressing folding and sorting proteins, in order to show that this represents a novel pathway counteracting prion propagation. Overall, our studies will provide mechanistic insights into basic cellular and molecular mechanisms which are relevant for neurodegenerative diseases and will result in novel targets for rational therapy against prion diseases and protein misfolding disorders.

描述（由申请人提供）：阐明prion传播和清除的细胞机制，以设计新的靶标在病毒疾病中进行干预的靶标的神经退行性疾病越来越多，这些疾病的数量越来越多，这些疾病是由于错误折叠的蛋白质的聚集而导致的，哪些蛋白质共享病理生理学机制。政治疾病是原型蛋白质错误折叠疾病，其发病机理仅与单个细胞蛋白（PRPC）的异常错误折叠有关。在该组中，王室疾病是独一无二的 它们是人和动物中发现的传染病。除了零星或遗传表现外，它们还可以通过感染获得并在物种之间传播，从而导致流行或流行病的情况（例如BSE/VCJD和CWD）。它们可以控制，但根除是不可能的。因此，必须了解传播和传播prion的分子和细胞的要求，以便为控制这些事件的设备合理策略。理解病毒病理生理学的进步将对其他蛋白质错误折叠疾病产生重大影响，因为这可能有助于阐明常见的细胞机制。这种理解具有基本的科学重要性，因为神经退行性疾病代表了我们老龄化社会中最大的健康问题之一，并且发现一般有效性的分子机制对于识别新靶标和发展理性疗法的发展至关重要。我们小组的长期目标是制定治疗性和预防性的反态策略。我们拥有的总体目标是研究prion感染的细胞和分子生物学，并利用获得的理解来描述新的靶标进行干预。我们将尝试的重点放在两种主要策略上。一个是prion的内源性细胞清除能力，另一个是靶向细胞同工型PRPC，这是神经变性的prion转化和执行的先决条件。我们的核心假设是，通过增加细胞来干扰prion传播是可行的 王室的清除。 AIM 1中的工作将证实我们的发现，可以通过化合物引起的自噬诱导来提高prion裂解，这是一种基本的降解和回收的蜂窝手机程序。拟议的工作旨在更好地了解基本的分子机制，并验证该发现在体内的治疗和转化潜力。 AIM 2和3中的工作解决了prion形成的细胞修饰符。我们发现，建立Prion感染需要一种基础自噬水平，我们建议自噬代表哺乳动物prion/prion样生物学中假定的分裂酶函数的生物学当量。我们的目标是在细胞和分子水平上证明这一点。 AIM 3中的工作的合理是，分泌途径中的蛋白质质量控​​制机制可以通过确定转化基底物的质量来直接影响prion依rion依。我们希望通过过度表达折叠和分类蛋白来操纵这一点，以表明这代表了一种新颖的途径来抵消prion传播。总体而言，我们的研究将提供与神经退行性疾病有关的基本细胞和分子机制的机械见解，并将导致针对抗原病毒疾病和蛋白质错误折叠式疾病的新靶标。